Production method

ABSTRACT

The present invention relates to a process for preparing compounds of general formula I 
     
       
         
         
             
             
         
       
     
     wherein R 1  and R 2  are defined as in claim  1,  the pharmaceutically acceptable salts and the solvates thereof, which may be prepared starting from compounds of general formula II 
     
       
         
         
             
             
         
       
     
     wherein R 1  is defined as in claim  1.

The present invention relates to a process for preparing compounds ofgeneral formula I

wherein R¹ and R² are as defined hereinbelow, the pharmaceuticallyacceptable salts and the solvates thereof, which can be preparedstarting from compounds of general formula II

wherein R¹ is as defined hereinbelow.

BACKGROUND TO THE INVENTION

1. Technical Field

The present invention relates to a process for preparing compounds ofgeneral formula I, which is based on a stepwise synthesis starting fromcompounds of general formulae III and IV. In addition, the inventionrelates to the compounds of general formulae III and IV per se, as theseare particularly suitable for preparing the compounds of general formulaI which have CGRP-antagonistic properties.

2. Prior Art

International Patent Applications PCT/EP03/11762 and PCT/EP2005/003094have already described compounds with CGRP-antagonistic properties aswell as some laboratory synthesis methods for preparing small amounts.

In addition, a process for preparing3-(4-piperidinyl)-2,3,4,5-tetrahydro-1,3-benzodiazepin-2(1H)-one isdescribed in European Patent Application No. 04017424.5.

DETAILED DESCRIPTION OF THE INVENTION

The compounds of general formulae III and IV are valuable startingmaterials for the synthesis of the compounds of general formula I whichhave CGRP-antagonistic properties.

The isolated intermediate stages occur as crystalline solids, which is amajor advantage for purification as well as for the separation of anymixtures of enantiomers that may occur.

The compounds of general formula II are valuable intermediate productsfor the synthesis of the compounds of general formula I which haveCGRP-antagonistic properties.

In a first aspect the present invention relates to a process forpreparing compounds of general formula II

wherein

R¹ denotes a group

wherein

-   -   R^(1.1) denotes H, C₁₋₃-alkyl, C(O)—O-benzyl, C(O)—O-tert.butyl        or benzyl, preferably benzyl,

comprising the steps of:

-   -   (a) coupling a compound of general formula III

-   -    wherein R¹ is as hereinbefore defined and X denotes a hydrogen        atom or a metal atom selected from among lithium, sodium and        potassium, preferably sodium, or a hydrate thereof, to a        compound of general formula IV

-   -    wherein R³ denotes an imidazole or triazole group, preferably        an imidazole group, which is attached via a nitrogen atom;    -   (b) isolating a compound of general formula II obtained in step        (a), preferably by crystallisation, from a solvent and    -   (c) optionally recrystallising a solid obtained in step (b) from        a suitable solvent.

In the coupling in step (a) preferably 1.0 equivalents of a compound ofgeneral formula III are reacted with 1.1 to 1.5 equivalents, preferablywith 1.1 equivalents, of a compound of general formula IV in a polarsolvent in the presence of a strong base. The polar solvent used may betert.-butanol or tetrahydrofuran or mixtures of these solvents, whilemixtures in the ratio 1:1 are preferred. The solvent is preferably addedin an amount of 1 to 3 mL/mmol of the compound used, preferably in anamount of 1 to 2 mL/mmol of the compound used.

The base is preferably added in an amount of 1.1 to 1.5 equivalents,preferably in an amount of 1.2 equivalents, based on the amount of thecompound of general formula III used. It is possible to use potassiumtert.butoxide, sodium tert.butoxide, lithium tert.butoxide or sodiumtert.amylate, while potassium tert.butoxide is preferably used accordingto the invention.

The crystallisation in step (b) and the recrystallisation in step (c)are carried out independently of one another, preferably in a polarsolvent. The polar solvent used may be, for example, water, ethanol,isopropanol or n-butyl acetate as well as mixtures of these solvents.According to the invention the crystallisation in step (b) is preferablycarried out from a mixture of n-butyl acetate and water in the ratio18:1 and the recrystallisation in step (c) is from a mixture ofisopropanol and water in the ratio 20:1.

In a second aspect the present invention relates to a process forpreparing compounds of general formula I

wherein

R¹ denotes a group

wherein

-   -   R^(1.1) denotes H, C₁₋₃-alkyl, C(O)—O-benzyl, C(O)—O-tert.butyl        or benzyl, preferably H or benzyl, and

R² denotes a secondary amine —NR^(2.1)R^(2.2), wherein

R^(2.1) and R^(2.2) independently of one another may be selected fromamong C₁₋₃-alkyl and benzyl, or

the group —NR^(2.1)R^(2.2) together forms a cyclic amine which may beselected from among morpholin-4-yl, 1-methylpiperazin-4-yl,1-benzylpiperazin-4-yl, 1-(C₁₋₃-alkylcarbonyl)-piperazin-4-yl,1-(tert.butyloxycarbonyl)-piperazin-4-yl,1-(benzyloxycarbonyl)-piperazin-4-yl, piperidin-1-yl andpyrrolidin-1-yl, the salts and solvates thereof, comprising the stepsof:

-   -   (a) coupling a compound of general formula III

-   -    wherein R¹ is as hereinbefore defined and X denotes a hydrogen        atom or a metal atom selected from among lithium, sodium and        potassium, preferably sodium, or a hydrate thereof, to a        compound of general formula IV

-   -    wherein R³ denotes an imidazole or triazole group, preferably        an imidazole group, which is attached via a nitrogen atom;    -   (b) reacting a product of general formula II obtained in step        (a)

-   -    wherein R¹ is as hereinbefore defined, with a compound of        general formula V

-   -    wherein R² is as hereinbefore defined; and    -   (c) in order to prepare compounds of general formula I wherein        R^(1.1) denotes a hydrogen atom, a protective group present is        optionally subsequently cleaved from a compound of general        formula I wherein R^(1.1) denotes one of the groups        C(O)—O-benzyl, C(O)—O-tert.butyl or benzyl.

In the coupling in step (a) preferably 1.0 equivalents of a compound ofgeneral formula II and 1.0 to 1.5 equivalents of a compound of generalformula III are suspended in a polar solvent and reacted at elevatedtemperature in the presence of a strong base.

The polar solvent used may preferably be tert.butanol or THF. The baseused may be selected from among potassium tert.butoxide, sodiumtert.butoxide, lithium tert.butoxide and sodium tert.amylate. Thereaction is preferably carried out at a temperature between 40 and 80°C.

The reaction described under step (b) above is preferably carried out atlow temperature in the presence of an amine and a condensing agent in apolar, aprotic solvent.

The amine used may be selected from among triethylamine,diisopropylethylamine, ethyldiisopropylamine and tributylamine. Thecondensing agent may be selected from among propanephosphonic anhydride,dicyclohexylcarbodiimide, carbonyldiimidazole, carbonylditriazole,2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium-tetrafluoroborate,1-ethyl-3-(3′-dimethylamino-propyl)-carbodiimide andchlorodimethoxy-triazine, optionally in the presence ofhydroxysuccinimide, hydroxybenzotriazole, p-nitrophenol orpentafluorophenol.

The polar aprotic solvent used may be THF or ethyl acetate. According tothe invention the reaction is preferably carried out at a temperaturebetween 0 and 25° C.

For the optional cleaving of a benzyl protective group in step (c), acompound of general formula I wherein R^(1.1) denotes a benzyl groupobtained in step (b), is dissolved in a polar solvent, such as forexample methanol, ethanol, water, acetone, tetrahydrofuran,dimethylformamide or propanol, and hydrogenated in a pressurisedreactor. The hydrogenation agent used may be Pd/C or Pd(OH)₂ forexample. Advantageous conditions for the hydrogenation are temperaturesof 40 to 80° C. and an excess hydrogen pressure of not more than 3 bar.After the catalyst has been filtered off the compound of general formulaI wherein R^(1.1) denotes a hydrogen atom may be obtained byconcentrating the solvent with the addition of another polar solvent,preferably ethanol.

In a third aspect the present invention relates to the compounds ofgeneral formula III

wherein

R¹ denotes a group

wherein

-   -   R^(1.1) denotes H, C₁₋₃-alkyl, C(O)—O-benzyl, C(O)—O-tert.butyl        or benzyl, preferably benzyl, and    -   X denotes a hydrogen atom or a metal atom selected from among        lithium, sodium and potassium, preferably sodium,

and the hydrates thereof.

A preferred third object includes the following compounds of formulaeIIIa to IIId:

No. Structure (1)

(2)

(3)

(4)

(5)

and the hydrates thereof.

Another preferred third object relates to the compound(αR)-α-hydroxy-3.5-dimethyl-4-(phenylmethoxy)-phenylpropionic acidmonosodium salt of formula IIIa

which occurs in crystalline form and is characterised by a high degreeof stability.

The crystalline compound of formula IIIa is characterised by acharacteristic melting point of T=237±3° C. The value given wasdetermined by Differential Scanning calorimetry (DSC: evaluated byonset, heating rate: 10° C./min) (DSC 821 of Mettler Toledo).

Another preferred third object of the present invention relates to thecrystalline compound of formula IIIa, characterised by a water contentof between 0.5 and 3%.

In a fourth aspect the present invention relates to a process forpreparing compounds of general formula III

wherein

R¹ denotes a group

wherein

-   -    R^(1.1) denotes H, C₁₋₃-alkyl, C(O)—O-benzyl, C(O)—O-tert.butyl        or benzyl, preferably benzyl, and the hydrates thereof, and    -   X denotes a hydrogen atom or a metal atom selected from among        lithium, sodium and potassium, preferably sodium,

characterised in that

-   -   (a) (diethoxyphosphinyl)-hydroxyacetic acid is reacted with        cyclohexane dimethylketal and optionally in the presence of an        acid in a non-polar aprotic solvent and the diethyl        (3-oxo-1,4-dioxaspiro[4.5]dec-2-yl)-phosphonate is obtained by        azeotropic distillation of the methanol released;    -   (b) the diethyl (3-oxo-1,4-dioxaspiro[4.5]dec-2-yl)-phosphonate        obtained under (a) is reacted in the presence of lithium        chloride and a strong base with a compound of general formula VI

-   -    wherein R^(1.1) is as hereinbefore defined, and a compound of        general formula VII

-   -    thus obtained wherein R^(1.1) is as hereinbefore defined, is        optionally recrystallised from a polar solvent;    -   (c) a compound of general formula VII obtained under (b) is        dissolved in a solvent and combined with a strong inorganic        base;    -   (d) a compound of general formula VIII

-   -    formed as an intermediate under (c), wherein R^(1.1) is as        hereinbefore defined, is reduced in the presence of a base and a        reducing agent to form a compound of general formula IX

-   -    wherein R^(1.1) is as hereinbefore defined; and    -   (e) a compound of general formula III wherein X denotes a metal        atom selected from among lithium, sodium and potassium,        preferably sodium, is isolated by the addition of lithium        hydroxide, sodium hydroxide solution or potassium hydroxide        solution, preferably sodium hydroxide solution.

In the reaction in step (a) preferably 1.0 equivalents of(diethoxyphosphinyl)-hydroxyacetic acid are reacted with 2.0 to 2.5equivalents of cyclohexane-dimethylketal. The non-polar aprotic solventmay be selected from among toluene, o-xylene, m-xylene and p-xylene aswell as corresponding mixtures of these solvents. Preferably, 1.0 to 3.0mL solvent/mmol (diethoxyphosphinyl)-hydroxyacetic acid are used.

The acid used in step (a) may preferably be selected from amongp-toluenesulphonic acid, methanesulphonic acid, sulphuric acid andbenzene-sulphonic acid.

The reaction in step (b) is preferably carried out in a solvent which isselected from among tetrahydrofuran, tert.butylmethylether, dioxane,mono-, di-, tri- and polyethyleneglycol ether. The strong base used inthe reaction may be selected from among 1,4-diazabicyclo[2,2,2]octane(DABCO), potassium tert.butoxide, tetramethylguanidine and1,8-diazabicyclo[5,4,1]undec-7-ene (DBU).

If the compounds of general formula VII are crystalline, they maysubsequently be recrystallised from a polar solvent which is selectedfrom among methanol, ethanol, propanol, isopropanol and n-propanol.According to the invention methanol is preferably used for therecrystallisation.

The reaction described under step (c) hereinbefore is preferably carriedout in methanol, ethanol, propanol, isopropanol or tetrahydrofuran or ina mixture of these solvents.

The strong inorganic base may be selected from among lithium hydroxide,potassium hydroxide, sodium hydroxide and caesium hydroxide.

The base mentioned under step (d) hereinbefore is selected from amongtriethylamine, diisopropylethylamine and pyridine.

The reducing agent also described under step (d) may be selected fromamong β-chlorodiisopinocampheylboran, Alpine-borane andmethyl-CBS-oxazaborolidine.

In a fifth aspect the present invention relates to the compounds ofgeneral formula IV

wherein R³ denotes an imidazole or triazole group, preferably animidazole group, which is attached via a nitrogen atom.

A preferred fifth object encompasses the following compound of generalformula IVa:

which is obtained in crystalline form and is characterised by a highdegree of stability.

The crystalline compound of formula IVa is characterised by acharacteristic melting point of T=218 ±3° C. The value stated wasdetermined by Differential Scanning calorimetry (DSC: evaluated byonset, heating rate: 10° C./min) (DSC 821 of Mettler Toledo).

In a sixth aspect the present invention relates to a process forpreparing compounds of general formula IV

wherein R³ denotes an imidazole or triazole group, preferably animidazole group, which is attached via a nitrogen atom, characterised inthat

-   -   (a) carbonyldiimidazole or carbonylditriazole, preferably        carbonyldiimidazole, is dissolved in a polar aprotic solvent and        is reacted at elevated temperature with        1,3,4,5-tetrahydro-3-(4-piperidinyl)-2H-1,3-benzodiazepin-2-one;        and    -   (b) a crude product formed in step (a) is crystallised by the        addition of another polar aprotic solvent, if R³ denotes an        imidazole group.

The solvent mentioned under step (a) hereinbefore may be selected fromamong acetone, acetonitrile, tert.butylmethylether,N,N-dimethylacetamide, dimethylformamide, dimethylsulphoxide, pyridineand N-methylpyrrolidone.

The polar aprotic solvent mentioned under step (b) hereinbefore may beselected from among tert.butylmethylether and dimethylformamide.

A seventh embodiment of the present invention relates to a process forpreparing compounds of general formula V

wherein

R² denotes a secondary amine-NR^(2.1)R^(2.2), wherein

R^(2.1) and R^(2.2) independently of one another may be selected fromamong C₁₋₃-alkyl and benzyl, or

the group-NR^(2.2)R^(2.2) together forms a cyclic amine which may beselected from among morpholin-4-yl, 1-methylpiperazin-4-yl,1-benzylpiperazin-4-yl, 1-(C₁₋₃-alkylcarbonyl)-piperazin-4-yl,1-(tert.butyloxycarbonyl)-piperazin-4-yl,1-(benzyloxycarbonyl)-piperazin-4-yl, piperidin-1-yl andpyrrolidin-1-yl, preferably morpholin-4-yl,

comprising the steps of:

-   -   (a) reaction of 1-benzylpiperidone with an amine of general        formula X

H—NR^(2.1)R^(2.2),   (X)

-   -    wherein R^(2:1) and R²² are defined as hereinbefore, in a        solvent and in the presence of an acid;    -   (b) reduction in the presence of a reducing agent and isolation        of the resulting product of general formula XI

-   -    wherein R^(2:1) and R²² are defined as hereinbefore and    -   (c) removal of the benzyl protecting group from a compound of        general formula XI obtained under (b) in a polar solvent and in        the presence of a reducing agent and    -   (d) isolation of a compound of general formula XII obtained        under (c)

-   -    wherein R^(2:1) and R²² are defined as hereinbefore.

In the reaction in step (a) preferably 1.0 equivalents of1-benzylpiperidone are reacted with 1.0 to 1.5 equivalents, preferably1.1 to 1.2 equivalents, of an amine of general formula X.

The solvent used may be selected from among 2-methyltetrahydrofuran,toluene, tetrahydrofuran, tert.butylmethylether, dioxane, mono-, di-,tri- and polyethyleneglycol ether, while tetrahydrofuran is preferablyused. Preferably, 2.0 to 5.0 mL of solvent are used per mmol of1-benzylpiperidone, particularly preferably 2.0 to 3.0 mL of solvent areused per mmol of 1-benzylpiperidone. The acid used may preferably beselected from among p-toluenesulphonic acid, methanesulphonic acid,sulphuric acid and benzenesulphonic acid; preferably, p-toluenesulphonicacid is used.

The reduction in step (b) is carried out in the presence of a reducingagent which may be selected from among sodium triacetoxyborohydride andsodium borohydride; preferably, sodium triacetoxyborohydride is used.The reducing agent may be added in an amount of from 1.0 to 3.0equivalents, preferably from 1.0 to 2.0 equivalents, particularlypreferably 1.5 equivalents, based in each case on the amount of1-benzylpiperidone used.

The cleaving of a benzyl protecting group described under step (c) froma compound of general formula XI may be carried out in a polar solventsuch as, for example, methanol, ethanol, water, acetone,tetrahydrofuran, dimethylformamide or propanol. The solvent is added inan amount of from 1.5 to 5.0 mL/mmol of compound of general formula XIused, preferably from 2.0 to 4.0 mL/mmol of compound of general formulaXI used, particularly preferably 2.5 mL/mmol of compound of generalformula XI used.

The reduction is carried out in a pressurised reactor. The hydrogenatingagent used may be Pd/C or Pd(OH)₂, for example. Advantageous conditionsfor hydrogenation are temperatures from 40 to 80° C. and an excesshydrogen pressure of not more than 3 bar.

The isolation of a compound of general formula XII may be carried out bycrystallisation, for example.

Terms and Definitions Used

Within the scope of this application, in the definition of possiblesubstituents, these may also be represented in the form of a structuralformula. If present, an asterisk (*) in the structural formula of thesubstituent is to be understood as being the linking point to the restof the molecule.

The subject-matter of this invention also includes the compoundsaccording to the invention, including the salts thereof, wherein one ormore hydrogen atoms, for example one, two, three, four or five hydrogenatoms, are replaced by deuterium.

By the term “secondary amine” is meant an amino group of general formula—NR^(2.1)R^(2.2), wherein the groups R^(2.1) and R^(2.2) independentlyof one another may be selected from among C₁₋₃-alkyl and benzyl, or thegroup —NR^(2.1)R^(2.2) together forms a cyclic amine which may beselected from among morpholin-4-yl, 1-methylpiperazin-4-yl,1-benzylpiperazin-4-yl, 1-C₁₋₃-alkylcarbonyl-piperazin-4-yl,1-tert.butyloxycarbonyl-piperazin-4-yl,1-benzyloxycarbonyl-piperazin-4-yl, piperidin-1-yl and pyrrolidin-1-yl.

Examples include:

By the term “C₁₋₃-alkyl” (including those which are part of othergroups) are meant branched and unbranched alkyl groups with 1 to 3carbon atoms. Examples include: methyl, ethyl, n-propyl or iso-propyl.The following abbreviations may optionally also be used for theabove-mentioned groups: Me, Et, n-Pr, i-Pr, etc.

The compounds of general formula I may contain basic groups such as e.g.amino functions. They may therefore be present as internal salts, assalts with pharmaceutically useable inorganic acids such as for examplehydrobromic acid, phosphoric acid, nitric acid, hydrochloric acid,sulphuric acid, methanesulphonic acid, ethanesulphonic acid,benzenesulphonic acid, p-toluenesulphonic acid or organic acids such asfor example malic acid, succinic acid, acetic acid, fumaric acid, maleicacid, mandelic acid, lactic acid, tartaric acid or citric acid.

The invention relates to the respective compounds optionally in the formof the individual optical isomers, mixtures of the individualenantiomers or racemates, in the form of the tautomers as well as in theform of the free bases or the corresponding acid addition salts withpharmacologically acceptable acids—such as for example acid additionsalts with hydrohalic acids—for example hydrochloric or hydrobromic acidor organic acids—such as for example tartaric acid, fumaric acid,diglycolic acid or methanesulphonic acid.

EXPERIMENTAL SECTION EXAMPLE 1Diethyl(3-oxo-1,4-dioxaspiro[4.5]dec-2-yl)-phosphonate (C)

In a reaction vessel with a descending condenser, 50 g (0.236 Mol)(diethoxy-phosphinyl)-hydroxyacetic acid (A) and 240 mL toluene aremixed at ambient temperature and then heated to 110° C. When the boilingtemperature of toluene is reached, a mixture of 71.7 mL (0.471 Mol)cyclohexane-dimethylketal (B) and 10 mL toluene are slowly addeddropwise, while the azeotrope of toluene and methanol is distilled off.After the addition has ended the reaction mixture is refluxed for 90minutes. Any solvent distilled off is replaced by the addition of 50 mLtoluene. In order to achieve total conversion, a further 10 mL (0.066Mol) of cyclohexane-dimethylketal (B) are added dropwise. The mixture isheated to a 110° C. for another hour and the solvent distilled off isreplaced by the addition of another 100 mL toluene. After the additionof another 120 mL toluene the solvent is distilled off in vacuo. Theresidue is taken up in 200 mL tert.butyl-methylether and successivelyextracted twice with 200 mL of 10% potassium carbonate solution, oncewith 250 mL of 30% sodium bisulphite solution and once with 150 mL of30% sodium bisulphite solution. After subsequent extraction with 40 mLsaturated saline solution the organic phase is dried and evaporateddown. Yield: 59 g (86% of theory)

EXAMPLE 2(3E)-3-[[3,5-dimethyl-4-(phenylmethoxy)phenyl]methylene]-1,4-dioxaspiro[4.5]decan-2-one(E)

4.2 g lithium chloride (0.1 Mol), 20.0 g (83.2 mmol) of4-benzyloxy-3,5-dimethylbenzaldehyde (D) and 31.62 g (108.2 mmol) ofdiethyl (3-oxo-1,4-dioxaspiro[4.5]dec-2-yl)-phosphonate (C) aresuspended in 130 mL tetrahydrofuran and cooled to −20° C. At thistemperature 12.5 mL (0.1 Mol) tetramethylguanidine are added dropwise.After the addition has ended the suspension formed is heated to ambienttemperature and stirred for 1 hour. After the addition of 190 mLtert.butyl-methylether the organic phase is washed with 150 mL water and30 mL saturated saline solution, dried and evaporated down. Theresulting yellow oil is taken up in 145 mL methanol and stirredintensively for 1 hour at −10° C., during which time a white solid isformed. The solid formed is suction filtered, washed twice with 20 mLmethanol/water (1:1) and dried at 45° C. Yield: 26.0 g (86% of theory)

EXAMPLE 3 (αR)-α-Hydroxy-3,5-dimethyl-4-(phenylmethoxy)-phenylpropionicacid-monosodium salt (G)

10.0 g (26.4 mmol) of(3E)-3-[[3,5-dimethyl-4-(phenylmethoxy)phenyl]methylene]-1,4-dioxaspiro[4.5]decan-2-one(E) are dissolved in 90 mL tetrahydrofuran and 10 mL ethanol. At 10° C.,26.4 mL (53 mmol) of 2N sodium hydroxide solution are added dropwise.The reaction mixture is heated to ambient temperature for 1 hour. Afterthe addition of 90 mL toluene the resulting 2-phase mixture is stirredfor 5 minutes. After separation of the phases the aqueous phase iscombined with 30 mL of 2N hydrochloric acid, combined with 13 g sodiumchloride and extracted with 40 mL 2-methyl-tetrahydrofuran. The organicphase is dried on sodium sulphate. The drying agent is filtered off andthe remaining substance is washed with 10 mL 2-methyl-tetrahydrofuran.The combined organic phases are combined with another 50 mL of2-methyl-tetrahydrofuran.

The solution of(2E)-343,5-dimethyl-4-(phenylmethoxy)phenyl]-2-hydroxy-2-propenoic acid(F) thus obtained is combined at 0° C. with 4.4 mL (32 mmol) oftriethylamine. After cooling to −20° C., 16.9 mL ofβ-chlorodiisopinocampheylboran (65% solution in hexane) are addeddropwise. After 2 hours at −20 to −30° C., 30 mL 2N hydrochloric acidand 50 mL ethyl acetate are added. After extraction and separation ofthe phases the organic phase is dried and evaporated down. The residueis dissolved in 150 mL tert.butyl-methylether and cooled to 0° C. Afterthe addition of 6.6 mL of 4N sodium hydroxide solution the suspensionformed is stirred for 1 hour and filtered. The isolated solid is dried.

Yield: 6.6 g (77% of theory)

ee value: 78%

chemical purity (HPLC): 97.5%

melting point: 237° C.

EXAMPLE 41-(1H-imidazol-1-yl-carbonyl)-4-(1,2,4,5-tetrahydro-2-oxo-3H-1,3-benzodiazepin-3-yl)-piperidine(J)

10 g (44.8 mmol) of carbonyldiimidazole (I) are in 40 mLdimethylformamide at 40 to 50° C. dissolved. Then 10.0 g (40.8 mmol) of1.3.4,5-tetrahydro-3-(4-piperidinyl)-2H-1,3-benzodiazepin-2-one (H) areadded batchwise. The suspension formed is liquefied by the addition of40 mL tert.butyl-methylether and cooled to ambient temperature. Afterthe addition of another 40 mL tert.butyl-methylether the suspension isfiltered, the isolated solid is washed with 100 mLtert.butyl-methylether and dried.

Yield: 12.9 g (93% of theory)

chemical purity (HPLC): 98.2%

melting point: 218° C.

EXAMPLE 5Ethyl(1R)-4-(1,2,4,5-tetrahydro-2-oxo-3H-1,3-benzodiazepin-3-yl)-1-carboxy-2-[3,5-dimethyl-4-(phenylmethoxy)phenyl]-1-piperidinecarboxylate(K)

10.527 g (31.8 mmol) of(αR)-α-hydroxy-3,5-dimethyl-4-(phenylmethoxy)-phenylpropionicacid-monosodium salt (G) and 11.88 g (35 mmol) of 1-(1H-imidazol-1-yl-carbonyl)-4-(1,2,4,5-tetrahydro-2-oxo-3H-1,3-benzodiazepin-3-yl)-piperidine(J) are suspended in 50 mL tert-butanol and tetrahydrofuran at ambienttemperature. The suspension is heated to 70 to 75° C., while 20 mLsolvent are distilled off. Then at 65° C. a 24% solution ofpotassium-tert-butoxide (16.4 g, 35 mmol) in tetrahydrofuran is addeddropwise. After 30 minutes at 70° C. a further 1.2 g (3.5 mmol) of1-(1H-imidazol-1-ylcarbonyl)-4-(1,2,4,5-tetrahydro-2-oxo-3H-1,3-benzodiazepin-3-yl)-piperidineare added. After another hour the reaction mixture is cooled to 45° C.and combined with 60 mL 2 N hydrochloric acid while cooling with ice.After the addition of 40 mL ethyl acetate and subsequent extraction thephases are separated. The organic phase is washed with 20 mL saturatedsaline solution and evaporated down. The residue is taken up in 180 mLn-butyl acetate and 10 mL water and refluxed for 1 hour. After coolingto ambient temperature the suspension is stirred for 12 hours andfiltered. The residue is washed with 20 mL n-butyl acetate and dried.

Yield: 15.8 g (87% of theory)

ee value: 80%

chemical purity (HPLC): 97.3%

The ee value can be increased to 95% by recrystallisation fromisopropanol/water (20:1).

EXAMPLE 6 4-[1-(phenylmethyl)-4-piperidinyl]-morpholine (N)

30 mL (0.162 Mol) 1-benzylpiperidone (L) and 16.1 mL (0.185 Mol)morpholine (M) are dissolved in 407 mL tetrahydrofuran at ambienttemperature. While cooling, 1.0 g (5 mmol) of p-toluenesulphonic acidand 14.6 mL glacial acetic acid are added, whereupon a jelly-likeprecipitate is formed. 52.19 g (0.246 Mol) sodium triacetoxyborohydrideare added while cooling with ice, during which time the reactiontemperature rises to 30° C. After 4 hours at 20° C., 90 mL water areadded dropwise. After another 30 minutes, 280 mL of 17% potassiumcarbonate solution are added. The mixture is stirred intensively, whilegas is observed to be given off. After separation of the phases theorganic phase is dried and evaporated down.

Yield: 33.0g (78% of theory)

EXAMPLE 7 4-(4-piperidinyl)-morpholine (O)

41.59 g (0.16 Mol) 4-[1-(phenylmethyl)-4-piperidinyl]-morpholine (N) aredissolved in 400 mL methanol, combined with 5.2 g palladium on activatedcharcoal (10%) and hydrogenated for 18 hours at ambient temperature with50 psi hydrogen. The catalyst is filtered off and the filtrate isevaporated down. A colourless oil remains, which crystallises after ashort time.

Yield: 25.29 g (93% of theory)

EXAMPLE 82-oxoethyl(1R)-4-(1,2,4,5-tetrahydro-2-oxo-3H-1,3-benzodiazepin-3-yl)-14[3,5-dimethyl-4-(phenylmethoxy)phenyl]methyl]-2-[4-(4-morpholinyl)-1-piperidinyl]-1-piperidinecarboxylate(P)

27.5 g (48.1 mmol) of ethyl(1R)-4-(1,2,4,5-tetrahydro-2-oxo-3H-1,3-benzodiazepin-3-yl)-1-carboxy-2-[3,5-dimethyl-4-(phenylmethoxy)phenyl]-1-piperidinecarboxylate(K) and 9.75 g (57.3 mmol) of 4-(4-piperidinyl)-morpholine (O) aredissolved at ambient temperature in 200 mL tetrahydrofuran. The solutionis cooled to 0 to 10° C. and combined with 16.1 mL (115.4 mmol) oftriethylamine. Then 37.2 mL (62.5 mmol) of propanephosphonic anhydride(50% solution in ethyl acetate) are added dropwise at this temperature.After one hour the reaction mixture is heated to ambient temperature.After the addition of 175 mL ethyl acetate the organic solution iswashed with 70 mL of 10% potassium carbonate solution and with 70 mLsaturated sodium chloride solution, dried and evaporated down.

Yield: 32.9 g (94% of theory)

chemical purity (HPLC): 90.9%

ee value: 99.7%

EXAMPLE 92-oxoethyl(1R)-4-(1,2,4,5-tetrahydro-2-oxo-3H-1,3-benzodiazepin-3-yl)-1-[[3,5-dimethyl-4-hydroxy)phenyl]methyl]-2-[4-(4-morpholinyl)-1-piperidinyl]-1-piperidinecarboxylate(Q)

31.1 g (43 mmol) of2-oxoethyl(1R)-4-(1,2,4,5-tetrahydro-2-oxo-3H-1,3-benzodiazepin-3-yl)-1-[[3,5-dimethyl-4-(phenylmethoxy)phenyl]methyl]-2-[4-(4-morpholinyl)-1-piperidinyl]-1-piperidinecarboxylate(P) are dissolved in 250 mL methanol and hydrogenated with 1.56 gpalladium on activated charcoal (10%) at 50° C. After the uptake ofhydrogen has ended the catalyst is filtered off and washed withmethanol. The filtrate is evaporated down with the addition of ethanol.

Yield: 27.4 g

chemical purity (HPLC): 92.4%

ee value: 98.8%

1-19. (canceled)
 20. A process for preparing a compound of the formula V

wherein R² denotes a secondary amine —NR^(2.1)R^(2.2), wherein R^(2.1)and R^(2.2) independently of one another are C₁₋₃-alkyl or benzyl, orthe group-NR^(2.1)R^(2.2) together forms a cyclic amine which isselected from the group consisting of morpholin-4-yl,1-methylpiperazin-4-yl, 1-benzylpiperazin-4-yl,1-(C₁₋₃-alkylcarbonyl)-piperazin-4-yl,1-(tert.butyloxycarbonyl)-piperazin-4-yl, 1-(benzyloxycarbonyl)-piperazin-4-yl, piperidin-1-yl and pyrrolidin-1-yl,comprising the steps of: (a) reacting 1-benzylpiperidone with an amineof the formula XH—NR^(2.1)R^(2.2),   (X)  wherein R^(2.1) and R^(2.2) are defined ashereinbefore, in a solvent and in the presence of an acid; (b) reducingthe product of step (a), by contact with a reducing agent to produce aproduct of the formula XI

 wherein R^(2.1) and R^(2.2) are defined as hereinbefore and (c)removing the benzyl protecting group from the compound of formula XIobtained in step (b) by treating the compound of formula XI with areducing agent in a polar solvent, to yield a compound of the formula V.21. The process according to claim 20, wherein R² denotes a secondaryamine —NR^(2.1)R^(2.2), wherein the group —NR^(2.1)R^(2.2) togetherforms morpholin-4-yl.